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Definitions

• the present invention relates to a vector.
• HTLN-BLN human T-cell leukemia virus-bovine leukemia virus group
• RSN Rous sarcoma virus
• MMTN mouse mammary tumour virus
• MN murine leukemia virus
• HTLN human T-cell leukemia virus
• one population of newly synthesised retroviral RNA remains unspliced to serve as the genomic RNA and as mRNA for gag and pol.
• the other population is spliced, fusing the 5' portion of the genomic RNA to the downstream genes, most commonly env.
• Splicing is achieved with the use of a splice donor positioned upstream of gag and a splice acceptor near the 3' terminus of pol
• the intron between the splice donor and splice acceptor that is removed by splicing contains the gag and pol genes. This splicing event creates the mRNA for envelope (Env) protein.
• mice ecotropic retrovirus unlike its amphotropic relative normally only infects mouse cells, to specifically infect particular human cells.
• Replacement of a fragment of an Env protein with an erythropoietin segement produced a recombinant retrovirus which then binds specifically to human cells that express the erythropoietin receptor on their surface, such as red blood cell precursors (Maulik and Patel 1997 " ' Molecular Biotechnology: Therapeutic Applications and Strategies” 1997 Wiley-Liss Inc. pp 45).
• the adenovirus is a double-stranded, linear DNA virus that does not go through an RNA intermediate.
• the natural target of adenovirus is the respiratory and gastrointestinal epithelia, generally giving rise to only mild symptoms.
• Serotypes 2 and 5 are most commonly used in adenoviral vector systems and are normally associated with upper respiratory tract infections in the young.
• Adenoviral vectors are also capable of transducing non dividing cells. This is very important for diseases, such as cystic fibrosis, in which the affected cells in the lung epithelium, have a slow turnover rate. In fact, several trials are underway utilising adenovirus-mediated transfer of cystic fibrosis transporter (CFTR) into the lungs of afflicted adult cystic fibrosis patients.
• CFTR cystic fibrosis transporter
• a retroviral vector wherein the functional intron is positioned so that it is capable of restricting expression of at least one of the NOIs at a desired target site.
• a retroviral vector wherein the target site is a cell.
• a hybrid viral vector system wherein the primary vector is obtainable from or is based on a adenoviral vector and/or the secondary viral vector is obtainable from or is based on a retroviral vector preferably a lentiviral vector.
• 15 vectors may be used to generate an adenoviral primary vector according to the invention encoding two or three transcription units for construction of the retroviral secondary vector.
• Transcription units as described herein are regions of nucleic acid containing coding sequences and the signals for achieving expression of those coding sequences independently of any other coding sequences.
• each transcription unit generally comprises at least a promoter, an enhancer and a polyadenylation signal.
• hypoxia is a powerful regulator of gene expression in a wide range of different cell types and acts by the induction of the activity of hypoxia-inducible transcription factors such as hypoxia inducible factor- 1 (HIF-1 ; Wang & Semenza 1993 Proc Natl Acad Sci 90:430), which bind to cognate DNA recognition sites, the hypoxia-responsive elements (HREs) on various gene promoters.
• hypoxia inducible factor- 1 HEF-1 ; Wang & Semenza 1993 Proc Natl Acad Sci 90:430
• HREs hypoxia-responsive elements
• Primary target cells for the vector system according to the invention include haematopoietic cells (including monocytes, macrophages, lymphocytes, granulocytes or progenitor cells of any of these); endothelial cells: tumour cells; stromal cells; astrocytes or glial cells; muscle cells; and epithelial cells.
• haematopoietic cells including monocytes, macrophages, lymphocytes, granulocytes or progenitor cells of any of these
• endothelial cells tumour cells; stromal cells; astrocytes or glial cells; muscle cells; and epithelial cells.
• the secondary viral vectors may also be targeted vectors.
• retroviral vectors this may be achieved by modifying the Env protein.
• the Env protein of the retroviral secondary vector needs to be a non-toxic envelope or an envelope which may be produced in non- toxic amounts within the primary target cell, such as for example a MMLV amphotropic envelope or a modified amphotropic envelope.
• the safety feature in such a case is preferably the deletion of regions or sequence homology between retroviral components.
• Transcription units as described herein are regions of nucleic acid containing coding sequences and the signals for achieving expression of those coding sequences independently of any other coding sequences.
• each transcription unit generally comprises at least a promoter, an enhancer and a polyadenylation signal.
• the promoter and enhancer of the transcription units encoding the secondary vector are preferably strongly active, or capable of being strongly induced, in the primary target cells under conditions for production of the secondary viral vector.
• the promoter and/or enhancer may be constitutively efficient, or may be tissue or temporally restricted in their activity.
• the packaging signal including part of the gag gene, remains in the vector genome.
• the defective retroviral genome contains a minimal packaging signal which does not contain sequences homologous to gag sequences in the first transcription unit.
• retroviruses for example Moloney Murine Leukaemia virus (MMLV)
• MMLV Moloney Murine Leukaemia virus
• the corresponding region of homology between the first and second transcription units may be removed by altering the sequence of either the 3' end of the pol coding sequence or the 5' end of env so as to change the codon usage but not the amino acid sequence of the encoded proteins.
• Extended deletions serve to provide additional cloning capacity for the introduction of multiple genes in the vector. For example a 25 kb deletion has been described (Lieber et al. 1996 J. Virol. 70: 8944-8960) and a cloning vector deleted of all viral genes has been reported (Fisher et al 1996 Virolology 217: 1 1- 22.) which will permit the introduction of more than 35kb of heterologous DNA.
• Such vectors may be used to generate an adenoviral primary vector according to the invention encoding two or three transcription units for construction of the retroviral secondary vector.
• the primary viral vector preferentially infects a certain cell type or cell types. More preferably, the primary vector is a targeted vector, that is it has a tissue tropism which is altered compared to the native virus, so that the vector is targeted to particular cells.
• the term "targeted vector” is not necessarily linked to the term "target cell”.
• the secondary viral vectors may also be targeted vectors.
• retroviral vectors this may be achieved by modifying the envelope protein.
• the envelope protein of the retroviral secondary vector needs to be a non-toxic envelope or an envelope which may be produced in non-toxic amounts within the primary target cell, such as for example a MMLV amphotropic envelope or a modified amphotropic envelope.
• the safety feature in such a case is preferably the deletion of regions or sequence homology between retroviral components.
• FIG. 3 which shows a diagrammatic representation of pL-SA-N
• Figure 4 which shows a diagrammatic representation of pL-SA-N with a splice donor deletion
• FIG. 13 which shows the restriction of gene expression to either packaging or transduced cells
• Figure 14 which shows the construction of a MLV pICUT Neo-p450 vector that restricts hygromycin expression to producer cells and 2B6 (a p450 isoform) expression to transduced cells;
• Figure 15 which shows a sequence comparison of mutant env (m4070A) with wild type MMLV sequence from the 3' end of the pol gene;
• Figure 17 which shows a restricted gene expression construct
• Figure 11 shows the pEICUT-Z ⁇ cZ sequence.
• VSAT1 (GGGCTATATGAGATCTTGAATAATAAAATGTGT)
• the second oligo. was in the reverse orientation and spanned a unique Pmel site (underlined):

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• 1999
  • 1999-03-22 GB GBGB9906615.1A patent/GB9906615D0/en not_active Ceased
• 2000
  • 2000-03-22 JP JP2000606769A patent/JP2002539797A/ja active Pending
  • 2000-03-22 KR KR1020017012059A patent/KR20020003215A/ko not_active Application Discontinuation
  • 2000-03-22 GB GB0120709A patent/GB2362886A/en not_active Withdrawn
  • 2000-03-22 CA CA002367488A patent/CA2367488A1/en not_active Abandoned
  • 2000-03-22 CN CN00805182A patent/CN1344326A/zh active Pending
  • 2000-03-22 EP EP00911135A patent/EP1163356A1/de not_active Withdrawn
  • 2000-03-22 WO PCT/GB2000/001091 patent/WO2000056910A1/en not_active Application Discontinuation
  • 2000-03-22 AU AU33128/00A patent/AU3312800A/en not_active Abandoned
• 2001
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